This is a continuing study of T cell function using synthetic polypeptide antigens. Previous studies have tested the usefulness of considering a specific interaction between antigen and MHC, i.e., of the agretope, as an explanation for both the phenomena of Ir genes and the concentration of the locations of T cell epitopes. These data demonstrate that the sites of T cell recognition and of antigen-MHC interaction are overlapping in the cytochrome c system. In addition, the apparent specificity of the antigen-MHC interaction varies for each individual T cell clone. Thus, despite the growing evidence that an antigen-MHC interaction takes place, our data imply that its usefulness as an explanation for the above phenomena is limited. In other studies, data have been collected concerning the VAlpha and VBeta genes expressed by T cells specific for pigeon cytochrome c and cross-reactive antigens. These data have suggested an alternative explanation for these Ir gene and epitope observations. We propose to test this hypothesis by further examination, using recombinant DNA technology, of TCR specific for antigens highly homologous to but poorly cross-reactive with pigeon cytochrome c. If the studies of TCR specific for these variant antigens reveal a common pattern of V gene expression, we propose to extend the experiments to include the V genes expressed by auto- and allo-reactive T cells specific for the IEK and IEb MHC products to understand better the effects of thymic education on the T cell repertoire. Recent reports of both analytical and experimental work have suggested that the capacity of different portions of protein antigens to be presented to T cells is highly variable and maybe dependent on the ability of the individual products of antigen degradation to assume an amphipathic conformation. This suggestion offers an alternative explanation for the above noted observations; one based on the physiology of antigen processing. To test this hypothesis we will identify the locations of epitopes seen by murine and human T cell responses to a larger protein antigen that lacks any self homolog, diphtheria toxin. Potential clinical benefits that may accrue from the human studies are also discussed.